The nutritional adequacy of low-protein diets (LPD) and the mechanism for successful adaptation in normal subjects and CRF patients have not been carefully examined. Unfortunately, nitrogen balance (BN) only measures overall response without revealing metabolic adjustments nor whether long- term accommodation to an inadequate protein intake will occur after loss of body protein. In normal subjects, successful adaptation to LPD includes a reduction in amino acid oxidation (without a decrease in protein synthesis and/or degradation) yielding more efficient use of protein. Currently, the mean requirement for normal subjects (0.6 g ketoacids (VLPD-EAA or VLPD-KA) are being used in patients with CRF, but factors in CRF or the supplement may change the adaptive response to LPD. In rats, uremic acidosis increases protein degradation, branch-chain amino acid (BCAA) oxidation and nitrogen excretion. Energy metabolism also affects protein metabolism in experimental uremia. We therefore, plan to assess the utility of the reciprocal pool method for determining BCAA and protein metabolism and to compare results obtained using L[1-13C] leucine and [1-13C] valine (Specific Aims a and 2). We will then compare the short- and long-term (6 months) adaptive response of CRF and normal subjects to different levels of dietary protein using BN, BCAA turnover, calorimetry and the double-labeled water technique (Specific Aims 3 and 4). To assess the nutritional response to VLPD-KA, the optimal tracer technique will be determined and then short- and long-term adaptive responses compared to CRF patients consuming a conventional LPD (Specific Aims 5 and 6). If a nutritional advantage is found with the VLPD-KA diet, it will be compared to a VLPD-EAA regimen (Specific Aims 7 and 8). Finally, the influence of the metabolic acidosis of uremia on the nutritional responses of CRF patients will be examined (Specific Aims 9). This nutritional responses of CRF patients will be examined (Specific Aims 9). This comprehensive evaluation should provide insight into mechanisms of adjustment to and nutritional requirements of normal subjects and CRF patients, and will identify factors that may modify protein requirements, (i.e. energy expenditure or acidosis).